Press Releases for 1994

Gene Replacement Prevents Lupus-Like Autoimmune Disease in Mice

Researchers have found that replacing a single defective gene can correct
a lupus-like autoimmune disease in mice. The gene, called lpr or Fas ,
plays a key role in a process known as programmed cell death or apoptosis.
Apoptosis enables the body to eliminate unnecessary, damaged, or potentially
harmful cells. This research may open the door to new treatments targeted to
specific defects in lupus.

"Before this cure was engineered in mice, it was unclear that this single
gene could account for many of the problems of an autoimmune disease," says
lead researcher Dr. John D. Mountz of the University of Alabama at Birmingham,
whose findings are reported in the March 15 issue of Proceedings of the
National Academy of Sciences . "The development of many autoimmune diseases
involves the concerted influence of several genes," says Dr. Susana Serrate-Sztein. "The
beauty of these results is that they show that if you know what the most important
gene defect is, gene therapy or other treatments that correct that specific
defect may be feasible for diseases like lupus. A lot of effort is being spent
in identifying those genes in humans," says Serrate-Sztein, Chief of the Rheumatic
Diseases Branch at the National Institute of Arthritis and Musculoskeletal
and Skin Diseases.

This research was supported by the National Institute of Arthritis and Musculoskeletal
and Skin Diseases, a component of the National Institutes of Health (NIH),
as well as by NIH's National Institute of Allergy and Infectious Diseases and
the Department of Veterans Affairs.

In the immune system, apoptosis is responsible for eliminating white blood
cells with the potential to attack the body's own tissues. Normally, the immune
system detects these "self-reactive" cells, and they are destroyed by apoptosis
before they can do any harm. If apoptosis is defective, self-reactive cells
will survive and may cause autoimmune diseases such as lupus. Some of these
white blood cells produce autoantibodies--antibodies directed against the body's
own cells and cell components.

Lupus is characterized by inflammation that causes redness, pain, swelling,
and tissue injury in different parts of the body. These include the joints,
skin, kidneys, lungs, heart, nervous system, and blood vessels. The signs and
symptoms of lupus differ from one person to another, and the disease can range
from mild to life-threatening. Lupus primarily affects women of childbearing
age, at a ratio of nine women to each man. In the United States, lupus is three
times more common in black women than in white women.

The mice used for this research, a mutant strain known as MRL -lpr/lpr , "develop
many features of human lupus, including kidney, joint, and lung disease," says
Mountz. "They also develop autoantibodies characteristic of human lupus," he
says. In addition, these mice develop lymphoproliferative (lpr) disease, that
is, they produce abnormally high numbers of lymphocytes. MRL -lpr/lpr mice
have a defect in the Fas ( lpr ) gene that leads to drastically
reduced production of the Fas apoptosis protein. The Fas protein, located on
cell surfaces, receives the orders that tell a cell to self-destruct. Activation
of Fas sets off a program of events within the cell that lead to that cell's
death.

Mountz, Dr. Jianguo Wu, and their colleagues at the University of Alabama
and the Uniformed Services University of the Health Sciences in Bethesda, Maryland,
showed that when the defective fas gene is replaced with a normal Fas gene,
the mice no longer develop signs of disease. The researchers genetically engineered
the mice to correct the defect in Fas production in white blood cells called
T cells. In these Fas transgenic mice, the lymphoproliferative disease
and kidney disease seen in the MRL -lpr/lpr mutant mice was eliminated,
and autoantibody levels were reduced.

Preliminary research suggests that defects in apoptosis may also occur in
people with lupus. Mountz and his colleagues are pursuing their research on
lupus in both humans and mice. "The studies in mice and humans go hand in hand," says
Mountz. "It is easy to test treatments in mice. We found one way to cure the
mice; our goal is to find ways to cure the mice that would be applicable to
humans, leading to safe and novel human therapies" he says.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases
leads and coordinates the Federal biomedical research effort in lupus by conducting
and supporting research projects, research training, clinical trials, and epidemiologic
studies, and by disseminating information on research results.

# # #

Reference: Jianguo Wu, Tong Zhou, Jinju Zhang, Jin He, William C. Gause, and
John D. Mountz. Correction of accelerated autoimmune disease by early replacement
of the mutated lpr gene with the normal Fas apoptosis gene
in the T cells of transgenic MRL -lpr/lpr mice. Proceedings of
the National Academy of Sciences , March 15, 1994.